This project proposes to train a DVM/PhD clinician-scientist and prepare her for success in a career as an independent scientist in the field of translational biomedical research. Specifically, the proposal addresses a gap in the understanding of the species barriers empirically observed in the transmission of prion diseases, invariably fatal neurodegenerative diseases of many species, including humans, domestic animals and wildlife. The aims described in this application will provide more information about the molecular underpinnings of prion disease species barriers, making it more feasible to predict and prevent trans-species transmission of prion diseases, particularly to humans. Specific Aims. 1) Define the role of protein interactions (between the pathologic prion protein and the normal prion protein) in determining the species barrier of bovine spongiform encephalopathy and chronic wasting disease prions. 2) Assess the new host effect and demonstrate prion species adaptation using a simplified protein interaction model. 3) Determine the role of the prion protein amino acid sequence in maintenance of prion disease species barriers. Application to Public Health. A better understanding of prion disease species barriers is important to any predictive models or preventative measures for trans-species prion transmission. Bovine spongiform encephalopathy is known to have crossed the species barrier to humans through the consumption of infected beef in the form of variant Creutzfeld-Jakob disease. The propensity of other prion diseases to infect humans is unclear, particularly chronic wasting disease, which infects deer and elk and is the only prion disease that is rapidly and easily transmissible in nature. This proposal may help understand this risk and identify preventative measures. Research Training Program. This proposal outlines training for the applicant in an established, combined DVM/PhD medical training program at Colorado State University. The applicant will complete a rigorous DVM curriculum while meeting the requirements to obtain a PhD in microbiology, immunology and pathology, which include at least three publications, a preliminary examination and a dissertation. This training plan will prepare the applicant for success in a career as an independent clinician-scientist in the field of translational medicine. Successful completion of the program will rely on exceptional mentorship from the sponsor and co-sponsor, as well as from a network of other advisors, a well-established DVM/PhD program, an innovative and relevant research plan, and determination on the part of the applicant.